US2023233476A1PendingUtilityA1

Nanoparticle pharmaceutical compositions with reduced nanoparticle size and improved polydispersity index

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Assignee: SIRNAOMICS INCPriority: Sep 22, 2021Filed: Sep 23, 2022Published: Jul 27, 2023
Est. expirySep 22, 2041(~15.2 yrs left)· nominal 20-yr term from priority
Inventors:Wookhyun KimDaniel MutisyaDavid Michael Evans
A61K 9/5146A61K 31/713A61K 9/5192B82Y 5/00A61K 47/34A61K 9/1272C12N 15/88B82Y 40/00
53
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Claims

Abstract

Methods of making and using nanoparticle pharmaceutical compositions comprising histidine-lysine copolymers are provided. The solutions spontaneously form nanoparticles when mixed with nucleic acids such as siRNA. Methods are provided where the pH of the nucleic acid solution is controlled prior to mixing leading to a reduction in nanoparticle diameter to a desirable range, typically 100-150 nm, and Polydispersity Index (PDI), both of which improve transport into target cells to improve the efficacy of gene silencing.

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A pharmaceutical composition prepared by microfluidic mixing of a nucleic acid solution having a pH of between about 4.0 and 6.9, and a solution of a histidine lysine copolymer having a pH of between 5.5 and 6.0,
 wherein said mixing of said composition results in nanoparticles formed, and   wherein at least 40%, at least 45%, at least 50%, at least 55% or at least about 60% of said nanoparticles formed have a diameter in a range selected from the group consisting of between about 40 and about 200 nm, between about 50 and about 150 nm, between about 50 and about 100 nm, and between about 60 and about 90 nm.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the pH of the nucleic acid solution is between about 5.0 and about 6.5. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the pH of the nucleic acid solution is between about 4.0 and about 5.0. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein said nucleic acid solution comprises one or more siRNA, miRNA and/or mRNAs. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the histidine-lysine copolymer is selected from the group consisting of HKP, HKP(+H), H 3 K4b, and H 3 K8b. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the nucleic acid solution comprises at least one siRNA. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the polydispersity index (PDI) of the nanoparticles is between about 0.02 to about 0.06. 
     
     
         8 . A method of preparing a pharmaceutical nanoparticle composition, comprising mixing a nucleic acid solution having a pH of between about 4.0 and 6.9, and a solution of a branched histidine-lysine copolymer having a pH of between 5.5 and 6.0 wherein the ratio of histidine-lysine copolymer to nucleic acid is between about 2.5:1 to about 3:1 (w/w). 
     
     
         9 . The method according to  claim 8 , wherein the nucleic acid solution has a pH selected from the group consisting of between about 4.0 and about 6.9, between about 6.0 and about 6.6, between about 5.5 and about 6.2, between about 4.5 and about 5.2, between about 4.0 and 5.0 and between about 4.0 and about 4.7. 
     
     
         10 . The method according to  claim 8 , wherein the histidine-lysine copolymer is HKP(+H). 
     
     
         11 . The method according to  claim 8 , wherein said histidine-lysine solution comprises ammonium acetate, wherein said ammonium acetate is present in an amount selected from the group consisting of: between about 11 and about 20 percent; between about 17 and about 20 percent; between about 14 and about 17 percent; between about 12 and about 14 percent; and between about 11 and about 14 percent. 
     
     
         12 . The method according to  claim 8 , wherein said histidine-lysine solution comprises Na 2 PO 4  (sodium phosphate), wherein said Na 2 PO 4  is present in in the composition between about 1 and about 2 mM (w/w). 
     
     
         13 . A method of treating a subject suffering from a disease, comprising administering to the subject a pharmaceutical composition comprising a nanoparticle composition according to  claim 1 , wherein said nucleic acid is an siRNA that reduces expression of a gene associated with said disease. 
     
     
         14 . The method according to  claim 13  wherein said disease is cancer. 
     
     
         15 . The method according to  claim 14 , wherein said cancer is selected from the group consisting of isSCC, BCC, H&N, liver, NSCLC, other solid tumors, pancreatic, colon, breast, prostate and CNS tumors. 
     
     
         16 . The method according to  claim 13  wherein said disease is an infection. 
     
     
         17 . The method according to  claim 13 , wherein said subject is a mammal. 
     
     
         18 . The method according to  claim 17 , wherein said mammal is a human.

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